1. Field of Invention
This invention relates to metal-based coordination complexes, and more particularly to metal-glycoprotein complexes that are particularly useful as therapeutic and diagnostic agents,
2. Description of Related Art
Photodynamic therapy (PDT) is currently an active area of research for the treatment of diseases associated with hyperproliferating cells such as cancer and non-malignant lesions. The development of new photodynamic compounds (PDCs or photosensitizers, PSs) for photodynamic therapy (PDT) has been increasingly focused on metallosupramolecular complexes derived from metals. For example, WO 2013158550 A1 and WO 2014145428 A2 disclose metal-based PDCs useful as in vivo diagnostic agents, as therapeutic agents for treating or preventing diseases that involve unwanted and/or hyperproliferating cell etiology, including cancer, as agents for treating infectious diseases, and as agents for pathogen disinfection and/or sterilization. U.S. Pat. No. 6,962,910, U.S. Pat. No. 7,612,057, U.S. Pat. No. 8,445,475 and U.S. Pat. No. 8,148,360 disclose supramolecular metal complexes capable of cleaving DNA when irradiated low energy visible light with or without molecular oxygen.
Delivery of metal-based coordination complexes and PDCs to biological targets can pose a challenge, which many have attempted to address.
For example, US 20120264802 discloses photosensitizer compounds based on functionalized fullerenes useful in targeted PDT, and methods of use thereof.
WO 2013020204 A1 discloses biodegradable polymeric nanoparticles comprising an inner core formed of a photodynamic agent capable of being activated to generate cytotoxic singlet oxygen. These nanoparticles have anti-cell proliferation activity and are useful in treating both cancerous and non-cancerous conditions including actinic keratosis, psoriasis and acne vulgaris. Preferably, the photodynamic agent is a hypocrellin B derivative while the polymeric nanoparticle comprises polyglycolic acid, polylactic acid or poly(lactide-co-glycolide). Hypocrellin-comprising nanoparticles are demonstrated to be activated by light or hydrogen peroxide.
US20110288023 discloses modified Transferrin (Tf) molecules and conjugates of the Tf molecules with a therapeutic agent. Also disclosed are methods of treating cancer wherein the therapeutic agents are chemotherapeutic agents. The modified Tf molecules improve the delivery of the conjugated therapeutic agent to a target tissue.
WO 2002094271 A1 discloses a homogeneous conjugate for targeting and treating diseased cells wherein the conjugate comprises an anti-cancer drug and a targeting protein, wherein said anti-cancer drug is selected from the group consisting of heat sensitizers, photosensitizers and apoptosis inducing compounds, a method for making such a conjugate, and methods for using the conjugate. The targeting protein is preferably transferrin.
U.S. Pat. No. 7,001,991 discloses a homogeneous conjugate for targeting and treating diseased cells wherein the conjugate comprises an anti-cancer drug and a targeting protein, wherein said anti-cancer drug is selected from the group consisting of heat sensitizers, photosensitizers and apoptosis inducing compounds, a method for making such a conjugate, and methods for using the conjugate. The targeting protein is preferably transferrin.
U.S. Pat. No. 7,809,428 discloses PDT methods for treatment of vulnerable plaques by selectively targeting and/or eliminating the inflammatory components of vulnerable plaques. In a preferred embodiment, photosensitizer compositions are coupled to macromolecular carriers that target T cells of vulnerable plaques. These macromolecular carriers can be targeted to, for example, IL-10, receptor, monocyte inflammatory protein-1 and receptors thereof and transferrin. Such macromolecular carriers can be, for example, antibodies against these biomolecules, ligands binding the same or analogs thereof, including, but not limited to monoclonal antibodies that recognize CD1, CD2, CD3, CD4, CDS, CD6, CD7, CDB, CD25, CD28, CD44, CD71 or transferrin.
Large (>500 Da) PSs are difficult to apply topically. Non-selectivity of delivery is another problem. Various patch- and film-based topical application formulations and methods of enhanced delivery of PSs directly into cancer cells have been proposed to overcome both difficulty of delivery of large (>500 Da) PS molecules and non-selectivity of the delivery. They include various patch- and film-based topical application formulations (Donnelly et al 2009), redox activation (Graf, Lippard, 2012), receptor-mediated delivery (Nkepang et al., 2014), photoinduced delivery (Chen et al., 2014; Yin et al., 2014; Sardar et al., 2014), liposomes (Temizel et al., 2014; Muehlmann et al., 2011), and delivery using nanoparticles including fullerenes (Biju, 2014; Yuan, Liu, 2014; Zhen et al., 2014; Wong et al., 2013; Yang et al., 2014; He et al., 2014). Combining of transferrin with fullerenes is also proposed (Zhang et al., 2015) as well as conjugation of PS-loaded liposomes with many molecules (folate, growth factors, glycoproteins such as transferrin, glycolipids) receptors for which are upregulated in cancer cells (Muehlmann et al., 2011; Nkepang et al., 2014). PEGylated AIPcS4-loaded liposomes conjugated with transferrin were used against cervical cancer cells (Gijsens et al., 2002). Exploration of Tf conjugation on the efficiency of liposome-encapsulated PS Foscan, a chlorine-based photosensitizer, in PDT of esophageal cancer was, however, not successful, likely due to the destabilization of the liposomes (Paszko et al., 2013).
Protein-based delivery systems include systems based on albumin (nanoparticles system), small heat shock protein, viral capsid and apoferritin (protein cage systems) used for doxorubicin delivery, soy protein (film-based system) for methylene blue delivery (MaHam et al., 2009). Apoferritin (i.e. Ferritin that is not combined with iron, a protein of 450 kDa) was used to encapsulate various cytostatic anticancer drugs: doxorubicin, carboplatin, cisplatin, daunorubicin although immune response to apoferritin may be a drawback (Heger et al., 2014). Among PCs, encapsulation of Methylene blue into apo-ferritin allowed increasing singlet oxygen production and enhancement of cytotoxic effects on cells (Heger et al., 2014, review).
The use of transferrin with liposomes containing aluminum phthalocyanine tetrasulfonate (LiposomesAlPcS4) is disclosed by Derycke et al., 2014; Gaspar et al., 2012.
None of the foregoing references explicitly propose the use of transferrin in combination with metal-based photosensitizers.
Despite the foregoing developments, it is still desired to provide improved compositions and methods for delivering PDCs to biological targets. It is further desired to provide increased efficacy of selective uptake of PDCs by biological targets. It is further desired to improve intracellular uptake of Ruthenium, Ruthenium-Rhodium and Osmium-based photosensitizers predominantly by cancer cells and tumor tissues. It is further desired to increase PDC efficacy at longer wavelengths. It is further desired to improve absorbance, ROS production and PDT effect of the Ruthenium, Ruthenium-Rhodium and Osmium-based photosensitizers. It is further desired to improve the PDT effect in hypoxia.